Vitamin E δ-tocotrienol in Patients with Pancreatic Ductal Neoplasia
A Phase I Safety, Pharmacokinetic, and Pharmacodynamic Presurgical Trial
of Vitamin E δ-tocotrienol in Patients with Pancreatic Ductal Neoplasia
Received 31 July 2015
Received in revised form 23 October 2015
Accepted 11 November 2015
Available online 14 November 2015
Background: Vitamin E δ-tocotrienol (VEDT), a natural vitamin E from plants, has shown anti-neoplastic and chemoprevention activity in preclinical models of pancreatic cancer. Here, we investigated VEDT in patients with
pancreatic ductal neoplasia in a window-of-opportunity preoperative clinical trial to assess its safety, tolerability,
pharmacokinetics, and apoptotic activity.
Methods: Patients received oral VEDT at escalating doses (from 200 to 3200 mg) daily for 13 days before surgery
and one dose on the day of surgery. Dose escalation followed a three-plus-three trial design. Our primary endpoints were safety, VEDT pharmacokinetics, and monitoring of VEDT-induced neoplastic cell apoptosis
(ClinicalTrials.gov number NCT00985777).
Findings: In 25 treated patients, no dose-limiting toxicity was encountered; thus no maximum-tolerated dose
was reached. One patient had a drug-related adverse event (diarrhea) at a 3200-mg daily dose level. The effective
half-life of VEDT was ~4 h. VEDT concentrations in plasma and exposure profiles were quite variable but reached
levels that are bioactive in preclinical models. Biological activity, defined as significant induction of apoptosis in
neoplastic cells as measured by increased cleaved caspase-3 levels, was seen in the majority of patients at the
400-mg to 1600-mg daily dose levels.
Interpretation: VEDT from 200 to 1600 mg daily taken orally for 2 weeks before pancreatic surgery was well tolerated, reached bioactive levels in blood, and significantly induced apoptosis in the neoplastic cells of patients
with pancreatic ductal neoplasia. These promising results warrant further clinical investigation of VEDT for
chemoprevention and/or therapy of pancreatic cancer.